The present invention relates in general to the field of xcex1-haloenamine chemistry, processes for the preparation of xcex1-haloenamines and, in one embodiment, to xcex1-haloenamine reagents supported by an organic or inorganic material which, under a defined set of conditions, renders the supported reagent sufficiently insoluble to enable separation of the reagent from a mixture.
xcex1-Haloenamine reagents are used in a number of synthetic reactions. For example, they are used to convert carboxylic acids to acid halides, alcohols to halides, sugars to sugar halides, and thiophosphoryl compounds to the corresponding phosphoryl halides. xcex1-haloenamine reagents offer advantages over other reagents for such conversions, particularly under neutral conditions and in those instances in which the substrate for the reaction contains one or more sensitive functionalities.
Despite these advantages, haloenamines are not being used to their full potential for a variety of reasons. Among these reasons are synthetic challenges. Ghosez et al. (Angew. Chem. Int. Ed. Engl. 1969, 8, 454) disclosed a route which involved the reaction of tertiary amides with phosgene followed by the dehydrochlorination of the intermediate xcex1-chloroiminium salts with triethylamine. According to Ghosez et al., the hazard associated with the use of large amounts of phosgene as well as the ban on phosgene in many laboratories led them to re-examine the preparation of xcex2-disubstituted-xcex1-chloroenamines; more recently, Ghosez et al. (Tetrahedron 54 (1998) 9207-9222) reported a synthetic route which was said to be conceptually the same as the previous one: it involved the reaction of a tertiary amide with a chlorinating agent followed by the elimination of hydrochloric acid from the resulting xcex1-chloroiminium salt. The halogenating agents tried by Ghosez et al. were thionyl chloride, diphosgene, triphosgene, phosphorous oxychloride, and phosphorous oxybromide. Of these, only phosphorous oxychloride was said to be suitable for the preparation of large amounts of xcex1-chloroenamines. Thionyl chloride was said to be unsuitable. Diphosgene and triphosgene were said to be suitable although in both cases a minor by-product was produced. As a result, Ghosez et al. stated that phosphorous oxychloride would probably supersede phosgene as the halogenating agent. Ghosez et al. also reported that they succeeded in preparing the corresponding xcex1-bromoenamines which, until then, they said were only available by halide exchange. Despite the advances reported by Ghosez et al., the conversion of a tertiary amide to an xcex1-chloroiminium salt, particularly when the nitrogen substituents are bulky can be difficult.
Recent advances in molecular biology, chemistry and automation have resulted in the development of rapid, high throughput screening (HTS) protocols to synthesize and screen large numbers of compounds for a desired activity or other desirable property in parallel. These advances have been facilitated by fundamental developments in chemistry, including the development of highly sensitive analytical methods, solid state chemical synthesis, and sensitive and specific biological assay systems. As a result, it is now common to carry out such reactions, in parallel, in a multi-well micro titer plate or other substratum having a plurality of wells for containing a reaction mixture, e.g., 96, 384 or even a greater number of wells. To date, however, xcex1-haloenamine reagents have not been provided in a form which would enable rapid, automated use and purification from such reaction mixtures.
One aspect of the present invention, therefore, is an improved process for the preparation of xcex1-haloenamines. The resulting xcex1-haloenamines may be used in a wide variety of synthetic schemes, such as the conversion of hydroxy-containing compounds and thiol-containing compounds to the corresponding halides. If immobilized onto a support, the resulting xcex1-haloenamines are particularly useful in high-throughput, automated and other systems where ease of separation is desired.
Briefly, therefore, the present invention is directed to an immobilized haloenamine reagent having the formula: 
wherein
R1 and R4 are independently hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy;
R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro, and
X is halo,
provided at least one of R1, R2, R3 and R4 comprises a support which enables physical separation of the reagent from a liquid mixture.
The present invention is further directed to a process for the preparation of an xcex1-haloenamine. The process comprises combining a tertiary amide with a pentavalent phosphorous halide in a solvent to form an xcex1-haloiminium salt and converting the xcex1-haloiminium salt to the xcex1-haloenamine with a base, the pentavalent phosphorous halide having at least two halogen atoms bonded to the pentavalent phosphorous atom.
The present invention is further directed to a process for dehydrating a non-aqueous solvent. The process comprises combining the solvent with an immobilized xcex1-haloenamine reagent.
The present invention is further directed to a process for converting a hydroxy-containing compound or a thiol-containing compound to the corresponding halide. The process comprises contacting the hydroxy-containing compound or thiol-containing compound with an immobilized xcex1-haloenamine. The hydroxy-containing compound may be selected, for example, from the group consisting of alcohols, carboxylic acids, silanols, sulfonic acids, sulfinic acids, phosphinic acids, phosphoric acids, and phosphates.
The present invention is further directed to an immobilized tertiary amide reagent having the formula: 
wherein
R1 and R4 are independently hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy; and
R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro,
provided at least one of R1, R2, R3 and R4 comprises a support which enables physical separation of the reagent
A. Preparation of xcex1-Haloenamines
In accordance with one aspect of the present invention, xcex1-haloenamines may be prepared from tertiary amides and pentavalent phosphorous halides. The tertiary amide reacts with the pentavalent phosphorous halide to produce a haloiminium salt which is then converted to the xcex1-haloenamine with a base.
In general, the tertiary amide may be any tertiary amide having a hydrogen atom bonded to the carbon which is in the alpha position relative to the carbonyl group of the tertiary amide and which does not interfere with the synthesis of or react with the xcex1-haloenamine. In one embodiment, the tertiary amide has the general formula: 
wherein
R1 and R4 are independently hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy; and
R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro.
Ordinarily, it will be preferred that R2 and R3 are other than hydrogen, such as alkyl or aryl to increase the stability of the reagent to a variety of conditions. Nevertheless, under some circumstances, provided one of R2 and R3 is sufficiently electron-withdrawing, the other may be hydrogen. Under other circumstances, each of R2 and R3 is electron withdrawing. In no event, however, may R2 and R3 each be hydrogen.
In one embodiment of the present invention, one of R1, R2, R3 and R4 comprises a support which enables physical seperation of the tertiary amide (or a derivative thereof) from a liquid mixture. The support may be, for example, any solid or soluble, organic or inorganic support which is conventionally used in chemical synthesis or any of a variety of assays. Such supports are described in greater detail elsewhere herein in connection with the supported xcex1-haloenamine reagents of the present invention. Preferably, it is polystyrene or a derivative thereof, for example, a 1% cross linked polystyrene/divinyl benzene copolymer.
The pentavalent phosphorous halide comprises at least two halogen atoms bonded to a pentavalent phosphorous atom. The three remaining valences are optionally occupied by bonds to carbon or halogen atoms. In general, therefore, the pentavalent phosphorous halide may be represented by the general formula P(X)2(Z)3 wherein each X is independently a halogen atom and each Z is independently a halogen atom or a carbon atom (which is part of a hydrocarbyl or substituted hydrocarbyl radical). For example, included within this general formula are pentavalent phosphorous halides in which the pentavalent phosphorous atom is bonded to two, three, four, or five halogen atoms selected from among chlorine, bromine and iodine. If fewer than five halogen atoms are bonded to the pentavalent phosphorous atom, the remaining valences are occupied by phosphorous-carbon bonds with the carbon being part of a hydrocarbyl or substituted hydrocarbyl radical, preferably phenyl or lower alkyl (e.g., methyl, ethyl or isopropyl). Although mixed halides are theoretically possible and within the scope of the present invention, for most applications it will generally be preferred that halogen atoms of only one type (e.g., only chlorine, bromine or iodine) be attached to the pentavalent phosphorous atom. Phosphorous pentachloride and phosphorous pentabromide are particularly preferred.
The xcex1-haloiminium salt resulting from the reaction of the tertiary amide and the pentavalent phosphorous compound may be converted to the xcex1-haloenamine with an amine base such as N,N-dialkyl anilines, trialkylamines, heterocyclic amines, pyridines, N-alkylimidazole, DBU and DBN. Tertiary amine bases such as triethylamine are generally preferred; other amine bases, however, such as substituted pyridines may be preferred under certain circumstances.
In general, therefore, and in accordance with one aspect of the present invention, xcex1-haloenamines of the present invention may be prepared in accordance with the following reaction scheme: 
wherein
R1 and R4 are independently hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, or substituted hydrocarbyloxy;
R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylcarbonyl, substituted hydrocarbylcarbonyl, hydrocarbyloxycarbonyl, substituted hydrocarbyloxycarbonyl, phosphinyl, thiophosphinyl, sulfinyl, sulfonyl, halo, cyano, or nitro, and
each X is independently chlorine, bromine or iodine; and
each Z is independently chlorine, bromine, iodine, hydrocarbyl or substituted hydrocarbyl.
The reaction may be carried out in acetonitrile, another solvent, or a mixture of solvents in which pentavalent phosphorous and the tertiary amide are sufficiently soluble. Other solvents include ethereal solvents (e.g., tetrahydrofuran, and 1,4-dioxane), esters (e.g., ethyl acetate), halogenated solvents (e.g., methylene chloride, chloroform and 1,2-dichloroethane), and under certain conditions, hydrocarbon solvents (e.g., toluene and benzene). If the solvent system comprises a mixture of solvents, the solvent system preferably comprises at least about 10% by weight, more preferably at least about 20% by weight acetonitrile.
If desired, the halogen atom, X, of the resulting xcex1-haloenamine (e.g., the chlorine atom of xcex1-chloroenamine or the bromine atom of xcex1-bromoenamine) may be displaced by another halogen atom to form other xcex1-haloenamine derivatives. Thus, for example, the chlorine atom of an xcex1-chloroenamine may be displaced by a bromide, fluoride or iodide atom. Similarly, the bromine atom of an xcex1-bromoenamine may be displaced by a fluoride or iodide atom. In general, the displacement may be carried out with an alkali metal halide (e.g., sodium, potassium, cesium or lithium bromide, fluoride or iodide).
B. Immobilized xcex1-Haloenamine Reagents
The immobilized xcex1-haloenamine reagent of the present invention comprises an xcex1-haloenamine component tethered to a support which enables physical separation of the reagent from a liquid composition. The xcex1-haloenamine component is tethered to the support by means of a linker and, optionally, a spacer. The immobilized xcex1-haloenamine reagents of the present invention generally correspond to the formula: 
wherein X is halogen, and R1, R2, R3 and R4 are as previously defined provided, however, at least one of R1, R2, R3 and R4 comprises a support which enables physical separation of the reagent from a liquid composition. In general, reactivity tends to be greater when R1, R2, R3 and R4 are less bulky and when R1, R2, R3 and R4 are alkyl or aryl. Preferably, therefore, R1, R2, R3 and R4 are independently hydrocarbyl or substituted hydrocarbyl, more preferably hydrocarbyl, still more preferably alkyl or aryl, provided at least one of R1, R2, R3 and R4 comprises a support which enables physical separation of the reagent from a liquid composition.
In one embodiment, the xcex1-haloenamine reagent support is a solid which is insoluble under all pertinent conditions. In another embodiment, the haloenamine reagent support is a composition which is selectively soluble in a solvent system; under a first set of conditions, the support is soluble but under a second set of conditions, the support is insoluble.
Insoluble polymers and other solid supports are typically the more convenient form since they may be easily separated from liquids by filtration. Such supports are routinely used in chemical and biochemical synthesis and include, for example, any insoluble inorganic or organic material that is compatible with chemical and biological syntheses and assays such as glasses, silicates, cross-linked polymers such as cross-linked polystyrenes, polypropylenes, polyacrylamides, polyacrylates and sand, metals, and metal alloys. For example, the xcex1-haloenamine reagent support may comprise poly(N,N-disubstituted acrylamide), e.g., poly(N,N-dialkyl substituted acrylamide) or a copolymer thereof. Preferred materials include polystyrene-based polymers and copolymers. Commercially available materials include TentaGel resin and ArgoGel (Bayer), both polystyrene/divinylbenzene-poly(ethylene glycol) graft copolymers (withxcx9c1-2% cross-linking) and 1% cross-linked polystyrene/divinylbenzene copolymer (ACROS) available in a range of particle sizes (e.g., 200-400 mesh).
In general, solid supports may be in the form of beads, particles, sheets, dipsticks, rods, membranes, filters, fibers (e.g., optical and glass), and the like or they may be continuous in design, such as a test tube or micro plate, 96 well or 384 well or higher density formats or other such micro plates and micro titer plates. Thus, for example, one, a plurality of, or each of the wells of a micro titer plate (96 well, 384 well or greater) or other multi well format substratum may have the xcex1-haloenamine reagent of the present invention tethered to its surface. Alternatively, beads, particles or other solid supports having an xcex1-haloenamine reagent of the present invention bound to its surface may be added to one, a plurality of, or each of the wells of a micro titer plate or other multi well substratum. Furthermore, if the solid support (whether in the form of a bead, particle, multi well micro titer plate, etc.) comprises poly(N,N-disubstituted acrylamide) or another polymer having tertiary amides chemically accessible at its surface, these tertiary amides may be converted to immobilized xcex1-haloenamines of the present invention using a pentavalent phosphorous halide as otherwise described herein; stated another way, the source of the tertiary amide, from which the immobilized xcex1-haloenamine of the present invention is derived may simply be a polymeric material comprising chemically accessible tertiary amides.
Solid-phase, polymer bound reagents, however, are not without their shortcomings. For example, phase differences obtained by heterogeneous, insoluble supports can create diffusion limitations due to the polymer matrix and this, in turn, can lead to reduced reactivity and selectivity as compared to classical, solution-phase synthesis. Furthermore, the insoluble nature of these supports can make synthesis and characterization of the polymer-reagent complex difficult. Accordingly, selectively soluble supports are preferred for some applications.
In general, any polymeric material which is soluble under one set of conditions and insoluble under a second set of conditions may be used as a selectively soluble support of the present invention provided this group does not interfere with the synthesis of or react with any of the reaction products or intermediates. Exemplary soluble polymers include linear polystyrene, polyethylene glycol, and their various polymers and copolymers derivatized with tertiary amides which may then be converted to xcex1-haloenamines. In general, however, polyethylene glycol is preferred. Polyethylene glycol exhibits solubility in a wide range of organic solvents and water but is insoluble in hexane, diethyl ether, and tert-butyl methyl ether. Precipitation using these solvents or cooling of polymer solutions in ethanol or methanol yields crystalline polyethylene glycol which can be purified by simple filtration. Attaching a haloenamine group to the polyethylene glycol thus allows for homogeneous reaction conditions while permitting for relatively easy purification.
The xcex1-haloenamine functionality or component of the xcex1-haloenamine reagent is preferably attached to the support by means of a linker. The only requirement is that the linker be able to withstand the conditions of the reaction in which the haloenamine reagent will be employed. In one embodiment, the linker is selectively cleavable under a set of conditions to permit cleavage of the enamine from the support. In another embodiment, the linker is not.
A great number of cleavable linkers have been developed over the years to allow many multistep organic syntheses to be performed. These linkers have generally been classified into several major classes of cleavage reaction (with some overlap between classes): (a) electrophilically cleaved linkers, (b) nucleophilically cleaved linkers, (c) photocleavable linkers, (d) metal-assisted cleavage procedures, (e) cleavage under reductive conditions, and (f) cycloaddition- and cycloreversion-based release. See, e.g., Guillier et al., Linkers and Cleavage Strategies in Sold-Phase Organic Synthesis and Combinatorial Chemistry, Chem. Rev. 2000, 100, 2091-2157.
More typically, the linker is non-cleavable and merely constitutes a chain of atoms connecting the xcex1-haloenamine to the solid support. The only requirement is that the sequence not react with any of the final products or intermediates. Thus, for example, any of the standard chemistries used to attach molecules to a solid support may be used to immobilize the xcex1-haloenamine or, more preferably, a tertiary amide precursor which is then converted to the xcex1-haloenamine using a pentavalent phosphorous halide. More specifically, a solid phase xcex1-chloroenamine reagent may be derived from a polystyrene supported tertiary amide and PCl5, with the polystyrene supported tertiary amide, in turn, being derived from polystyrene and a chloro-substituted tertiary amide in the presence of FeCl3 (see Example 2). Alternatively, styrene (or another polymerizable monomer) having a tertiary amide as a substituent on the phenyl ring may be polymerized to form a polymer having a pendant tertiary amide which, as described elsewhere herein, may be converted to an xcex1-haloenamine moiety using a pentavalent phosphorous halide, followed by treatment with a base.
Regardless of whether the linker is cleavable or non-cleavable, it may optionally include a spacer having a length and/or included moieties which provide the xcex1-haloenamine reagent with more xe2x80x9csolution-likexe2x80x9d properties and better solvent compatibility. In general, the spacer group, if present, may be any atom, or linear, branched, or cyclic series of atoms which distance the xcex1-haloenamine group from the support. The atoms, for example, may be selected from carbon, oxygen, nitrogen, sulfur and silicon. Preferred spacers include polyethylene glycol and alkyl chains.
In one embodiment of the present invention, one of R1 and R4 comprises a support and R2, R3 and the carbon atom to which they are attached are members of a carbocylic or heterocyclic ring: 
wherein R1, R2, R3, R4 and X are as previously defined and R5 is an atom or chain of atoms, which together with R2 and R3 define a carbocyclic or heterocyclic structure. If the structure is heterocyclo, the hetero atoms are preferably selected from oxygen and sulfur; basic nitrogens are preferably not included as a ring atom. In addition, the atom or chain of atoms comprising R5 may be substituted with one or more hydrocarbyl, substituted hydrocarbyl, hetero atom(s) or heterocyclo substituent. For example, together R2, R3, R5 along with the carbon atom to which R2 and R3 are attached may comprise a cycloalkyl ring such as cyclopentyl or a five or six-membered heterocyclic ring. In another embodiment, R3 comprises a support which enables physical separation of the reagent from a liquid composition, and any two of R1, R2, and R4 and the atoms to which they are attached are members of a heterocyclic ring: 
wherein R1, R2, R3, R4, and X are as previously defined and R5 is an atom or a chain of atoms, and R6 is a bond, an atom or chain of atoms, wherein R5, together with R1 and R4, or R6 together with R1 and R2, or R2 and R4 define a carbocyclic or heterocyclic structure. If the ring is heterocyclo, the hetero atoms are preferably selected from oxygen and sulfur; again, basic nitrogens are preferably not included as a ring atom. In each of these embodiments, R5 preferably comprises two or three chain atoms selected from carbon, oxygen and sulfur, and R6 is preferably a bond or an atom selected from carbon, oxygen and sulfur, thereby defining in each instance, a five or six membered heterocycle. In addition, the atom or chain of atoms or which R5 and R6 are comprised may optionally be substituted with one or more hydrocarbyl, substituted hydrocarbyl, hetero atom(s) or heterocyclo substituents.
C. Haloenamine Reactions
The xcex1-haloenamines of the present invention and, in particular, the immobilized xcex1-haloenamines of the present invention may be used in a variety of syntheses to convert hydroxy-containing and thiol-containing compounds to the corresponding halides. To avoid or at least minimize unwanted side reactions, the hydroxy or thiol-containing compounds preferably have an absence of other unprotected moieties which are also reactive with xcex1-haloenamines. For example, basic primary and secondary amine moieties will react with xcex1-haloenamines and thus, it is preferred that the hydroxy-containing or thiol-containing compound have an absence of unprotected basic primary and secondary amine moieties when it is reacted with an xcex1-haloenamine of the present invention. Suitable protecting groups are identified, for example, in Protective Groups in Organic Synthesis by T. W. Greene and P. G. M. Wuts, John Wiley and Sons, 3rd ed. 1999.
In one embodiment, an immobilized xcex1-haloenamine of the present invention is used to convert any of a wide range of carboxylic acids and thiocarboxylic acids to the corresponding acid halide. In a preferred embodiment, the carboxylic acids and thiocarboxylic acids have the formulae RcaCOOH and RcaC(O)SH and the resulting corresponding halides have the formulae RcaCOX wherein Rca is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo and X is halogen. For many applications, it will be preferred that X be chlorine or bromine, typically chlorine. In addition, Rca will often be alkyl, alkenyl, alkynyl, aryl, or heterocyclo optionally substituted with one or more substituents that do not react with the COX functionality or the haloenamine reagent, such as, one or more of halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers. For example, in one embodiment, X is chlorine or bromine, preferably chlorine, and Rca is heterocyclo. In general, however, it is preferred that compositions containing two carboxylic acid groups such as malonic acid be avoided since, upon reaction with an xcex1-haloenamine, they may form a cyclic structure which may not be readily released.
In another embodiment, an immobilized xcex1-haloenamine of the present invention is used to convert any of a wide range of alcohols to the corresponding halides, provided the alcohol is not a substituent of a carbocyclic, aromatic ring. In a preferred embodiment, the alcohol corresponds to the formula (Ra)3COH wherein each Ra is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
One particularly noteworthy class of alcohols which may be converted to the corresponding halides by reaction with immobilized xcex1-haloenamines of the present invention are sugars. The conversion of a suitably protected sugar to the corresponding halide is depicted in the following reaction scheme: 
wherein
X is F, Cl, or Br;
each Rxe2x80x3 is independently H, OZ, NHZ, SZ, or at least one additional saccharide unit;
Rxe2x80x2=H, (CH2)mOZ, (CH2)mNHZ, or (CH2)mSZ, or at least one additional saccharide unit;
m=0-1;
n=1-2; and
Z is a protecting group.
Thus, for example, the immobilized xcex1-haloenamine of the present invention may be used to convert the hemiacetal alcohol moiety of a monosaccharide, a disaccharide or a polysaccharide to a halide. Exemplary monosaccharides include allose, altrose, arabinose, erythrose, fructose, galactose, glucose, gulose, idose, lyxose, mannose, psicose, ribose, ribulose, sorbose, tagatose, talose, threose, xylose, xylulose, and erythrulose. Other exemplary sugars include the deoxy analogs, such as deoxyribose, rhamnose and fucose.
In another embodiment, an immobilized xcex1-haloenamine of the present invention is used to convert any of a wide range of silanols to the corresponding silyl halides. In a preferred embodiment, the silanol corresponds to the formula (Rsi)3SiOH and the resulting silyl halide corresponds to the formula (Rsi)3SiX wherein each Rsi is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, or heterocyclo, and X is halogen. For many applications, it will be preferred that X be chlorine or bromine, typically chlorine. In addition, Rsi will often be alkyl, alkenyl, alkynyl or aryl, optionally substituted with one or more moieties selected from halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers.
In another embodiment, an immobilized xcex1-haloenamine of the present invention is used to convert any of a wide range of sulfonic or sulfinic acids to the corresponding sulfonyl or sulfinyl halide. In a preferred embodiment, the sulfonic or sulfinic acid corresponds to the formula RsS(xe2x95x90O)nOH, and the corresponding halide corresponds to the formula RsS(xe2x95x90O)nX wherein Rs is hydrocarbyl, substituted hydrocarbyl, or heterocyclo, X is halogen and n is 1 or 2. For many applications, it will be preferred that X be chlorine or bromine, typically chlorine. In addition, Rs will often be alkyl, alkenyl, alkynyl or aryl, optionally substituted with one or more moieties selected from halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers.
In another embodiment, an immobilized xcex1-haloenamine of the present invention is used to convert any of a wide range of phosphinic acids, phosphonic acids or phosphates (or the thio analogs thereof) to the corresponding phosphoryl halide. In a preferred embodiment, the phosphinic acid, phosphonic acid or phosphate corresponds to the formula (Rp)uP(O)(OH)3-u and the corresponding halide corresponds to the formula (Rp)uP(O)X(3xe2x88x92u) wherein each Rp is hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, or heterocyclo, X is halogen, and u is 0-2. In an alternative embodiment, the phosphinc acid, phosphonic acid or phosphate is a thio analog corresponding to the formula (Rp)uP(O)(ZH)3-u and the corresponding halide corresponds to the formula (Rp)uP(xe2x95x90O)X(3-u) wherein Rp, X, and u are as previously defined and Z is O or S with at least one Z being S. For many applications, it will be preferred that X be chlorine or bromine, typically chlorine. In addition, Rp will often be alkyl, alkenyl, alkynyl or aryl, optionally substituted with one or more moieties selected from halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers. In general, however, it is preferred that phenylphosphinic acid (C6H5H2PO2) be avoided since, upon reaction with an xcex1-haloenamine, it forms a substance which is not readily released.
In another embodiment, an immobilized xcex1-haloenamine of the present invention is used to dehydrate a non-aqueous solvent. The process comprises combining the solvent with an immobilized xcex1-haloenamine reagent. The solvent may be any solvent which will not react with xcex1-haloenamines.
F. Definitions
The terms xe2x80x9chydrocarbonxe2x80x9d and xe2x80x9chydrocarbylxe2x80x9d as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include linear, branched or cyclic alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms. In addition, the hydrocarbyl moieity may be linked to more than one substitutable position of the tertiary amide or xcex1-haloenamine of the present invention; for example, R2 and R3 of the tertiary amide or xcex1-haloenamine may comprise the same chain of carbon atoms which, together with the carbon atoms to which R2 and R3 are attached define a carbocyclic ring.
The xe2x80x9csubstituted hydrocarbylxe2x80x9d moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers.
The term xe2x80x9cheteroatomxe2x80x9d shall mean atoms other than carbon and hydrogen.
Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
Unless otherwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
Unless otherwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
The terms xe2x80x9carylxe2x80x9d or xe2x80x9carxe2x80x9d as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
The terms xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
The terms xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers. In addition, the heterocyclo moieity may be linked to more than one substitutable position of the tertiary amide or xcex1-haloenamine of the present invention; for example, R1 and R2 of the tertiary amide or xcex1-haloenamine may comprise the same chain of atoms which, together with the atoms to which R1 and R2 are attached define a heterocyclo ring.
The term xe2x80x9cheteroaromaticxe2x80x9d as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy (preferably on aryl or heteroaryl rings), protected hydroxy, formyl, acyl, acyloxy, amino, amido, nitro, cyano, thiol, sulfides, sulfoxides, sulfonamides, ketals, acetals, esters and ethers.
The term xe2x80x9chydrocarbyloxy,xe2x80x9d as used herein denotes a hydrocaryl group as defined herein bonded through an oxygen linkage (xe2x80x94Oxe2x80x94), e.g., ROxe2x80x94 wherein R is hydrocarbyl.
xe2x80x9cDBUxe2x80x9d shall mean 1,8-diazabicyclo[5.4.0]undec-7-ene.
xe2x80x9cDBNxe2x80x9d shall mean 1,5-diazabicyclo[4.3.0]non-5-ene.
The following examples will illustrate the invention.